Substituted [1,3,5-triazinyl-(6)]-aminophenyl-arsonic acids and process for manufacture of same



Patented Segfi. 1 1 Q UNITE-D s'rAras PATENT SUBSTITUTED [1,3,5

AMINOPHENYL- ABSONIO ACIDS AND ISROOESS -FOR MANUFACTURE OFFICE TBIAZINII I i Ernst Albert Hermann Frledheim, Geneva,

Switzerland N Drawing. A pllcation December20 1939. o p In Switzerland D ecem- Serial No. 310,232. bet 23, 1938 Condensation products of triazines with various amines are known and used in the manufacture of dyes. However, derivatives or triazines \containing arsenic have hitherto not. been prepared. &

It has now been found that highly active therapeutic derivatives of [1,3,5-triazinyl-(6H- 'aminophenyl-arsonic acids can be obtained by reacting 1,3.5-triazine derivatives with phenylarsonic acid derivatives. This reaction may be eilected with halogen derivatives of triazine. The resulting reaction products can, ii. necessary,'be treated further by known methods with ammonia or alkyl-amines. Aminoand amino-halogenderivatives of 1,3.5-triazine are'also suitable for carrying out the present invention. The'reaction of 2,4,6-triamino-1,3,5-triazine with halogeno-phenyl-arsonic acids also gives rise to the products claimed in this invention.

The new compounds, which are to be employed -as medicinal preparations, have proved to exert an extraordinarily strong action in experimental trypanosomiasis in the mouse. The dose necessary for a lasting cure is up to ten times-smaller than in the case 01 the medicinal preparations derived from phenyl-arsonic acids whitherto used. The toxicity is low, that is, the therapeutic margin is considerable, which is particularly important in view of the danger of poisoning attending the use of remedies containing arsenic.

The new compounds are 1,3,5-triazine derivatives of the formula wherein x and Y are each a radical selected from the group consisting of halogen, NHz, NI-I Alk., N Alk.z, hydroxy-alkyl-amino, NHCHzCHOHCHzOH, and dialkyl-aminoalkyl-amino radicals, and A and B are selected from the group consisting of hydrogen, halogen, OH, O Alk., NOs, NHz, -NH Alia, N Alkn and alkyl radicals.

Claims. (01. 260-242) These compounds'may be prepared by reactin: a triazine derivative of the formula.

with a substituted phenyl-arsonic acid of the v formula:

WCcHz(A,B) AsOaHa one of Wand Z being a halogen radical and the other an amino radical. If desired, the reaction product may be treated with ammonia, alkyl amines, dialkyl amines, hydroxy-alkyl amines and dialkyl-amino-alkyl amines to react with any vremaining triazine halogen atoms.

' white reaction product which mm a suspension is filtered oil, washed with water and then with acetone.

The resulting p-[2,4-dichloro-1.3,5-triazinyl- (GH-aminophenyI-arsonic acid or the formula I? \N (ll-( .7 (Lira-Olson,

is a white powder insoluble in cold water, which can be dissolved in aqueous alkalis without colouration. The compound is insoluble in alcohol,

ether, benzene. The solution in concentrated sulphuric acid is colourless.

Example 2 The moist p- [2,4-dichlro-1,3,5-triazinyl-(6) aminophenyl-arsonic acid obtained in accordance with Example 1 is covered with times the quantity of 10% ammonia and shaken at 45 C. for 1 hour, whereby the product goes into complete solution. The excess ammonia is removed under reduced pressure. on acidification with hydrochloric acid p-[2-chloro-4-amino-1,3,5- triazinyl-(G)l-aminophenyl-arsonic acid of the formula I a is isolated in the form of small white crystals which are filtered off and washed with water and acetone.

The resulting compound is soluble in alkalis and also on warming with an excess of dilute mineral acid. It is insoluble in water, alcohol, ether and benzene. On heating to higher temperatures, the compound decomposes without having a definite melting point.

Example 3 The moist p-[2,4-dichloro-l,3,5-triazinyl-(6) aminophenyl-arsonic acid prepared in accordance with Example 1 is heated in an autoclave under pressure to 110-130 C. for about 2 hours with 10 times the quantity of 25% ammonia. When excess ammonia has been driven 01!, the product is treated with excess hydrochloric acid, whereupon the hydrochloride of p-[2,4-dia1nino- 1,3,5-triaziny1-(6) l-aminophenyl-arsonic acid of the formula 36.5 parts by weight of chloro-cyanuric-diamide ("Liebigs Annalen, vol. 10, year 1834, page 43) are boiled for about 2 hours under reflux with a solution of 31 parts by weight of atoxyl 'in 300 the compound obtained in accordance with Example 3.

The same compounds can be prepared if triamino-triazine (melamine) is reacted with halogeno-phenyl-arsonic acid (German patent specifications 205,449, 250,264. Mameli, Patta "Chemisches Zentralblatt" year 1909, 1, page 1091; year 1909, II, page 1856.)

Esample 5 10 parts by weight of a 17% solution of methylamine are poured over 1 part by weight of p [2,4 -,dichloro 1,3,5 triazinyl -(6)] aminoparts by weight of water whereupon the atoxyl disappears. The white reaction product is brought into solution by the addition of ammonia, The sulphate of p- [2,4-diamino-1,3,5-triazinyl- (6) l-aminophenyl-arsonic acid is precipitated from the filtered solution by sulphuric acid. The arsonic acid corresponds in all its properties with phenyl-arsonic acid obtained in accordance with Example 1 whereby solution sets in with evolution of heat. The solution is boiled until the excess of methylamine is driven oil. Sufiicient hydrochloric acid is then added to render the product just acid to congo paper upon which the hydrochloride of p- [2,4 dimethylamino-1,3,5-triazinyl-(6) l-aminophenyl-arsonic acid of the formula precipitates in small, white, crystalline needles on cooling. These needles are filtered off and washed with cold water. The compound is soluble in alkalis and dilute mineral acids without colouration; it is insoluble in ether and benzene.

Insteadof p-amino-phenyl-arsonic acid, its derivatives or isomers, such as, for instance, 4-oxy- 3-amino-(1) phenyl-arsonic acid-(l) or 2-oxy-' 4-amino-phenyl-arsonic acid may be employed in all the examples given above.

I claim:

1. A 1,3,5-triazine derivative of the formula wherein X and Y are each a radical selected from the group consisting of halogen, NHz, NH lower Alk., -.-N A1k.2, hydroxy-alkyl-amino, NHCHzCHOHCI-IzOH, dialkyl amino alkylamino radicals, and A and B are selected from the group consisting of hydrogen, halogen, OH, 0 Alk., --NO:, NHz, NH Alk., N Alka and alkyl radicals.

2. p-[2,4-diamino -l,3,5-triazinyl (6) ]--aminophenyl-arsonic acid of the formula II C-NH-O-AsOaHz v triazin derivative of the formula 3. m-EZSediamino-LS, triazinyl -(6) l-aminop-hydroxyphenyl-arsonic acid or the formula om, a. In a process for the preparation oi a 1,3,5-

wherein x and Y are each a radical selected from the group consisting of halogen, NHa, NH lower Alk., N Alk-z, hvdroxy-alkyl-amino, NHCHQCHOHCHQOH, dialhl amino alkylamino radicals, and A and B are selected from the group consisting of hydrogen, halogen, OH, Alk., NOz, N'Hz, NH Alk., N Alka and alkyl radicals, the step comprising reacting atrlazine derivative of the formula N/ II H C Z with a substituted phenyl-arsonic acid or the formula WCoH:(A.B) ASOaHz wherein one of Z and W is a halogen radicaland the other is an amino radical.

5. A process for the preparation of a 1,3,5- triazine derivative of the formula with a substituted phenyl-arsonic acid 0! the formula WC6H2 (AB) AsOam wherein one of F and W is a halogen radical and the other is an amino radical, and wherein one of D and E is a halogen radical and the other a radical selected from the group consisting of halogen, --NH3, NH lower Alk., N Alka, hy-

triazine or the formula 3 droiw albl-amino', sncmcuoncmdri, and dialkyl-amino-alkyl amino radicals, and treating the reaction product with a base selected from the group consisting oi ammonia, alkyl amines, v dialkyl amines, hydroxv-alkyl amines and dialkylamino-slkyl amines.

6. Process for the preparation oi 2,4-diamino-.

1,8,5-trlazine derivatives 0! the NH| T formula.

comprising reacting cyanuric chloride or the formula with aminophenyl-arsonic acids of the formula HzNCsHa(A,B)-As03Hz where A and B are selected from the group consisting of H, halogen, OH, 0 Alk., N02, NHz, NH A1k., N Alkn and alkyl, and subjecting the product to the action of ammonia.

7. Process for the preparation of 2,4-diamin0- 1,3,5-triazine derivatives of the formula comprising reacting 2-chloro-4,6-diamino-1,3,5-

with aminophenyl-arsonic acids or the formula H2N--CcHz(A,B)--ASO3H2 where A and B are selected from the group consisting of H, halogen, OH, O Alk., N02, NHz, NH Alk., N Alkxa and alkyl. a

8. Process for the preparation of p-[2,4-dichloro-1,3,5-triazinyl- (6) l-amlnophenyl arsonic acid oi. the formula O 01- C-NH ssoam comprising reacting cyanuric chloride with paminophenyl-arsonic acid.

9. Process for the preparation of p-[2,4-diamino-1,3,5-triazinyl-(6) l-aminophenyl arsonic acid or the formula comprising reacting cyanuric chloride with paminophenyl-arsonic acid in aqueous suspension and subsequent treatment of the p-[2,4-dichloro- 1,3,5 triazinyl- (6) l aminophenyl-arsonic acid with concentrated ammonia in aqueous solution.

11. Process for the preparation of .p-[2,4-diamino-1,3,5-triazinyl- (6) l-aminophenyl arsonic acid of the formula 1 H HzN-C /C NH ASOaH:

comprising reacting cyanuric chloride with paminophenyl-arsonic acid in aqueous suspension and subsequent treatment of the p-[2,4-dichloro- 1,3,5 triazinyl- (6) aminophenyl-arsonic acid with ammonia in aqueous solution under pressure.

12. Process for the preparation of p-[2,4-diamino-1,3,5-triazinyl-(6) l-aminophenyl arsonic acid of the formula 1 IIIH:

comprising reacting chloro-cyanuric diamide with p-aminophenyl-arsonic acid.

13. Process for the preparation of m-[2,4-diamino-1,3,5-triazinyl (6) 1 amino -p hydroxyphenyl-arsonic acid of the formula comprising reacting cyanuric chloride with 4-hydroxy-3-aminophenyl-arsonic acid and subsequent treatment of the m- [2,4-dichloro-1,3,5-triazinyl (6) amino phydroxy phenyl-arsonic acid so formed, with ammonia.

14. A process for the preparation of 1,3,5-triazine derivatives of the formula wherein X and Y are each a radical selected from the group consisting of halogen, NHz, NH lower Alk., N Alk.2, hydroxy-alkyl-amino, NHCHzCHOI-ICI-IzOH, dialkyl amino alkylamino radicals, and A and B are selected from the group consisting of hydrogen, halogen, OH, 0 Alk., NOz, NHz, NH Alk., N Alka and alky1 radicals, comprising reacting a triazine derivative of the formula wherein at least two of the radicals D, E and F are halogen radicals and the other is a radical selected from the group consisting of halogen, NHz, NH lower Alk., N Alka, hydroxy-alkylamino, NHCHzCHOHCI-IzOH and dialkylamino-alkyl-amino radicals, with a substituted amino-phenyl-arsonic acid of the formula NH2-CsHz (A,B) ASO3H2 wherein A and B are each selected from the group consisting of hydrogen, halogen, OH,

O Alk., NOz, NHa, NH Alk., -N Alka and alkyl radicals, and treating the reaction product with a base selected from the group consisting of ammonia, alkyl amines, dialkyl amines, hydroxyalkyl amines and dialkyl-amino-alkyl amines.

15. A process for the preparation of 1,3,5-triazine derivatives of the formula wherein X and Y are each a radical selected from the group consisting of halogen, NHz, NH lower Alk., N Alka, hydroxy-alkyl-amino,

NHCHzCHOHCI-IzOH, dialkyl amino alkylamino radicals, and A and B are selected from the group consisting of hydrogen, halogen, OH, --OAlk., NOa, NI-Ia, NH Alk., N Alka and alkyl radicals, comprising reacting a cyanuric halide of the formula halogen N N A H halogen- C-halogen with an aminophenyl-arsonic acid of the formula H2NC6H2(A,B)-ASOJH2 and reacting the resulting substituted p-[2,4-dihalogeno-1,3,5-triazinyl-(6)] with a base selected from the group consisting of ammonia, alkyl amines, 'dialkyl amines, hydroxy-alkyl amines and dialkyl-amino-alkyl amines.

ERNST ALBERT HERMANN FRIEDHEIM. 

